PMID- 19484784
OWN - NLM
STAT- MEDLINE
DCOM- 20091001
LR  - 20211203
IS  - 0008-543X (Print)
IS  - 0008-543X (Linking)
VI  - 115
IP  - 17
DP  - 2009 Sep 1
TI  - Synergistic effect of rapamycin and cisplatin in endometrial cancer cells.
PG  - 3887-96
LID - 10.1002/cncr.24431 [doi]
AB  - BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors modulate signaling 
      pathways involved in cell cycle progression, and phase 2 trials for endometrial 
      cancer are currently being conducted. Because rapamycin is known to enhance the 
      cytotoxicity of chemotherapeutic drugs, the authors' goal was to examine the 
      effects of rapamycin and cisplatin in endometrial cancer cell lines. METHODS: By 
      using Ishikawa and ECC-1 cells, cell proliferation was assessed after exposure to 
      rapamycin, cisplatin, or both in combination. The combination index (CI) was 
      calculated using the method of Chou and Talalay. Apoptosis was evaluated by flow 
      cytometry. Immunoblot analysis was performed to assess expression of S6 kinase 1 
      and the DNA mismatch repair proteins, MSH2 and MSH6. mTOR small interfering 
      (siRNA) was transfected into the cell lines, and proliferation and apoptosis were 
      assessed after exposure to cisplatin. RESULTS: Cisplatin inhibited growth in a 
      dose-dependent manner in both cell lines (median inhibition concentration of 8-13 
      muM). Simultaneous exposure of cisplatin in combination with rapamycin resulted 
      in a significant synergistic antiproliferative effect (CI < 1). Rapamycin 
      increased cisplatin-induced apoptosis and stimulated expression of MSH2 and MSH6 
      in the cisplatin-treated cell lines. Cell growth was significantly decreased in 
      cells transfected with mTOR siRNA and treated with cisplatin compared with either 
      alone (CI < 1). Transfection of mTOR siRNA did not induce apoptosis, but combined 
      treatment with cisplatin increased apoptosis over that of cisplatin alone. 
      CONCLUSIONS: The results of the current study provide evidence of a synergistic 
      relation between rapamycin and cisplatin in both inhibition of cell growth and 
      induction of apoptosis. This suggests that rapamycin and cisplatin may be a 
      rational combination of a targeted therapy for endometrial cancer.
FAU - Bae-Jump, Victoria L
AU  - Bae-Jump VL
AD  - Department of Obstetrics and Gynecology, University of North Carolina, Chapel 
      Hill, NC, USA. vbae@unch.unc.edu
FAU - Zhou, Chunxiao
AU  - Zhou C
FAU - Boggess, John F
AU  - Boggess JF
FAU - Gehrig, Paola A
AU  - Gehrig PA
LA  - eng
GR  - KL2 RR025746/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (G-T mismatch-binding protein)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.1.3 (MSH2 protein, human)
RN  - EC 3.6.1.3 (MutS Homolog 2 Protein)
RN  - Q20Q21Q62J (Cisplatin)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cisplatin/*administration & dosage
MH  - DNA-Binding Proteins/metabolism
MH  - Drug Screening Assays, Antitumor
MH  - *Drug Synergism
MH  - Endometrial Neoplasms/*drug therapy
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - MutS Homolog 2 Protein/metabolism
MH  - Protein Kinases/genetics/metabolism
MH  - Sirolimus/*administration & dosage
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
EDAT- 2009/06/02 09:00
MHDA- 2009/10/02 06:00
CRDT- 2009/06/02 09:00
PHST- 2009/06/02 09:00 [entrez]
PHST- 2009/06/02 09:00 [pubmed]
PHST- 2009/10/02 06:00 [medline]
AID - 10.1002/cncr.24431 [doi]
PST - ppublish
SO  - Cancer. 2009 Sep 1;115(17):3887-96. doi: 10.1002/cncr.24431.